Classes of ITD predict outcomes in patients with AML treated withFLT3inhibitors

Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML). ITD mutations of Fms-like tyrosine kinase 3 (FLT3) receptor increase kinase activity, and are associated with poor prognostic outcomes. Currently, several small-moleculeFLT3inhibitors (FLT3i) are in clinical trials for targeted therapy of high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence ofFLT3-ITD mutations in a patient might not guarantee effective clinical response to targeted inhibition ofFLT3kinase. Motivated by the heterogeneity ofFLT3-ITD mutations, we sought to investigate the effects ofFLT3-ITD structural features on response to treatment in AML patients. To this end, we developed HeatITup (HEAT diffusion for Internal Tandem dUPlication), an algorithm to efficiently and accurately identify ITDs and classify them based on their nucleotide composition into newly defined categories of “typical” or “atypical”. Typical ITDs insert sequences are entirely endogenous to theFLT3locus whereas atypical ITDs contain nucleotides exogenous to the wildtypeFLT3. We applied HeatITup to our cohort ofde novoand relapsed AML patients. Individuals with AML carrying typical ITDs benefited significantly more from FLT3i than patients with atypical ITDs, regardless of whether FLT3i was used after initial induction or at relapse. Furthermore, analysis of the TCGA AML cohort demonstrated improved survival for patients with typical ITDs treated with induction chemotherapy. These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing towards personalized treatment for AML patients.